摘要
研究背景:
大多数晚期恶性肿瘤需要接受以化疗为主的药物治疗。越来越多的证据表明,抗血管生成药物与化疗药物联合可提高疗效,带来生存受益。在晚期非小细胞肺癌(NSCLC)患者中进行的Ⅱ-Ⅲ期临床试验已证实,新型重组人血管内皮抑素(new rhendostatin—Endostar/恩度)联合NP(NVB+DDP)方案化疗可提高晚期非小细胞肺癌肿瘤缓解率(RR)、临床受益率(CBR),延长中位疾病进展时间(TTP),改善生活质量(QOL),提高总生存(OS);不良反应可耐受。
作为广谱的抗血管生成靶向药物,恩度最大的优势在于适应证较为广泛,无特定的病理要求。恩度联合化疗探索治疗其他晚期恶性肿瘤的研究也有报道,显示出一定的疗效。随着适应症的不断扩大,恩度治疗的安全性更显重要。
美国关于重组人血管内皮抑素(Endostatin)的Ⅱ期临床试验中,1例有冠心病史的患者发生了心肌梗死。国内关于恩度的Ⅰ-Ⅲ期临床试验结果显示,人体对恩度剂量限制性毒性(DLT)为各种心脏不良反应,发生率6.38%～13.2%;Ⅱ期临床试验中30mg/m~2组有1例发生了Ⅲ度心脏不良反应。
参芪注射液由党参、黄芪组方,大量临床前及临床研究表明,其与化疗药物合用具有协同抗肿瘤、保护骨髓功能及提高机体免疫力的作用;能减轻化疗药物所致的心脏毒性;临床使用安全。
目前尚无关于恩度联合化疗的心脏保护性研究的报道,更无中药对此的相关性研究。研究参芪注射液是否能减轻恩度联合化疗的心脏不良反应,协同恩度联合化疗是否有增效的作用,具有一定临床意义。
研究目的:
以晚期恶性肿瘤患者(非小细胞肺癌为主)作为研究对象,主要观察参芪注射液对新型重组人血管内皮抑素(恩度)联合化疗的心脏保护作用,同时观察其增效减毒的作用。
对象与方法:
采用前瞻性病例对照研究,共纳入07-3～08-2在我院及广州中医药大学附属第一医院肿瘤科住院、经病理确诊的Ⅲ、Ⅳ期恶性肿瘤患者48例,根据恩度联合化疗是否加用参芪注射液分成A、B组,观察各组治疗前后心肌酶谱、心电图、左室射血分数(LVEF)、血浆肌钙蛋白Ⅰ(troponinⅠ)和心脏血管不良反应及生活质量(QOL)、近期疗效(CR、PR、SD、PD)、疾病进展时间(TTP)。利用SPSS软件进行统计分析。
结果:
1.48例患者可评价心脏毒性,治疗前LVEF、血清心肌酶谱、血清肌钙蛋白均在正常范围,组间各项指标均衡性良好。
2.治疗后B组患者LVEF有所下降,而A组有所升高,全组未观察到超出正常者,统计分析显示治疗后组间变化差异有统计学意义(P值=0.0265);但两组内治疗前后自身比较左心射血分数变化不大,均无统计学差异。两组治疗后均观察到一定心肌酶谱升高,B组发生率较高,但无统计学显著性差异。两组治疗后均观察到一定心电图异常,B组发生率较高(41.66%),较治疗前有统计学意义(P＜0.05),但A组用药前后差异以及两组间用药后差异无统计学意义(P＞0.05)。两组均有一定心血管不良反应,B发生率略高,但无统计学差异(P＞0.05)。两组均无明显心功能异常。两组均有一定深静脉血栓发生率(P＞0.05)。曾使用过表皮生长因子抑制剂患者不良反应似乎偏大。
3.A组治疗后生活质量较前提高,有统计学意义(P＜0.05)。B组治疗后生活质量似有下降趋势,但无统计学意义(P＞0.05);两组之间治疗前及治疗后生活质量差异不明显(P＞0.05)。
4.本研究未见到参芪注射液对恩度联合化疗近期疗效、TTP的影响。38例非小细胞肺癌中治疗组与对照组RR分别为35%vs 27.78%(P＞0.05),治疗组与对照组CBR分别为70%vs 66.67%(P＞0.05);中位TTP分别为98天、61天(P＞0.05)。本文还观察到恩度联合化疗对其他肿瘤有一定疗效,因例数过少,难以反映总体疗效。
结论:
1、恩度联合化疗有一定心脏毒性,这种毒性与恩度相关。参芪注射液对恩度联合化疗有一定心脏保护作用,进一步改善生活质量,对疗效无明显影响。掌握好适应症、在推荐剂量下应用恩度联合化疗(无心肌毒性药物)心脏不良反应较轻,参芪注射液对其心脏保护作用未有充分体现。
2、推荐将心脏损伤监测指标作为使用恩度前的常规检测及治疗后的随访观察,以进一步观察恩度联合化疗的心脏不良反应、进一步掌握好使用恩度的适应症、提高恩度联合化疗的安全性。
3、值得进一步研究长期应用恩度、恩度联合心肌毒性药物化疗的安全性及与表皮生长因子抑制剂协同使用的安全性。
Background:
Most advanced cancer need to be treated with drugs,espasially chemo-combined therapy.More and more evidences show thatanti-angiogenesis drugs combined with chemotherapy drugs can improve the therapeutic effects, bring with the survival benefits.TheⅡ-Ⅲphase clinical trials in patients with advanced non-small cell lung cancer patients have confirmed that the new recombinant human endostatin(new rh-endostatin or Endostar)combined with NP(NVB+DDP)chemotherapy can improve tumor response rate(RR)and clinical benefit rate(CBR),prolong the median time to disease progression(TTP), improve the quality of life(QOL)and overall survival(OS),and the adverse reactions can be tolerated.
As a broad-spectrum anti-angiogenesis drug,the greatest advantage of endostar is that it has the wider indications,without specific pathology requirements to tumor.It has also been reported that the treatment of endostar combined with chemotherapy showed a certain efficacy in other advanced tumors. With the continuous expansion of indications,the security of Endostar treatment becomes particularly important.
In the United States,one patient with coronary heart disease suffered from myocardial infarction during the phaseⅡclinical trial of recombinant human endostatin.In China,the results ofⅠ-Ⅲphase clinical trials of endostar shows that,the dose limited talxity(DLT)of endostar in body is related to a variety of cardiac adverse reactions,with the rate of 6.38%~ 13.2%.And in phaseⅡclinical trial,Ⅲdegree cardiac adverse reactions have taken place in one patient in Group 30 mg/m2.
Shenqi injection is composed of Codonopsis pilosula and astragali.A large number of pre-clinical and clinical studies have proved that,Shenqi injection has the functions of killing tumor cells synergistically,protecting bone marrow,enhancing the body immunity,and reducing cardiac toxicity caused by chemotherapy.It has also been proved being a safty drug in clinical treatment.
At present,there is no research about the protection of the heart in treatment of endostar combined with chemotherapy be reported,especially the related research of traditional Chinese medicine.It shows certain clinical significance to investigate whether Shenqi injection can reduce the cardiac adverse reaction and whether it has a synergistic anti-tumor function in treatment of endostar combined with chemotherapy,
Purpose:Choose the patients with advanced cancer(mainly non-small cell lung cancer)as research object,observe the heart protective effect and synergistic effect of Shenqi injection during combination chemotherapy with endostar.
Patients and Method:Using prospective case-control study,48 patients diagnosed by histopathology with malignant tumor ofⅢorⅣstage from our hospital and the First Hospital of the Guangzhou University of Chinese Medicine during March,2007 to February,2008,were divided into two groups according to with(Group A)or without(Group B)Shenqi during endostar combination chemotherapy.Myocardial enzymogram,electrocardiogram,left ventricular ejection fraction(LVEF),plasma troponinⅠ(troponinⅠ),cardiovascular adverse reactions and the quality of life(QOL),the recent therapeutic effect(CR,PR,SD,PD),time to disease progression(TTP)were evaluated before and after the treatment。SPSS software was used for statistical analysis.
Result:
1、48 patients can evaluate the cardiac toxicity.The LVEF,serum myocardial enzymogram,serum troponinⅠare all in the normal range before treatment,and the equilibrium between two groups is belance.
2、LVEF of Group B patients is decreased after treatment,while Group A increased,the diversity has statistical significance(P=0.0265).And the LVEF of both Groups are in the nomal range.The diversity of LVEF between before and after treatment within Group A or within Croup B has no significant difference.It is observed a certain increase of myocardial enzymogram in both groups after treatment,with higher occurrence in Group B,but without statistical significant difference.Certain electro -cardiogram abnormality after treatment is observed in both groups,with higher occurrence rate in Group B(41.66%).The diversity in Group B between before and after treatment is significantly significant(P＜0.05).But the difference in group A between before and after treatment,and the difference between the two groups after treatment both have no significant significancy(P＞0.05).Both groups have a certain cardiovascular adverse reactions,with slightly higher rate in Group B,but no significant difference(P＞0.05).Both groups have no obvious cardiac dysfunction.It is observed a certain incidence of deep vein thrombosis in both groups(P＞0.05).It seems to show higher adverse reaction in patients who ever used epidermal growth factor inhibitors.
3、The quality of life in Group A has raised after therapy,with statistical significance(P＜0.05).The quality of life in Group B seems to show declining trend after treatment,but without statistical significance(P＞0.05).The diversity of quality of life between Group A and B both have no obvious difference before or after treatment.
4.The study did not show that Shenqi injection can influence the recent therapeutic effects and TTP with using in endostar - chemotherapy.Of 38 cases with non-small cell lung cancer,RR of treatment group vs control group was 35%vs 27.78%(P＞0.05),CBR of treatment group vs control group was 70% vs66.67%(P＞0.05).The median TTP were 98 days and 61 days respectively(P＞0.05). It also observed that endostar - chemotherapy have certain effect on other tumors.And because the number of the cases is too small,it can not reflect the overall effect.
Conclusion:
1.Endostar combined chemotherapy caused certain cardiotoxity,which is related to Endostar.Shenqi injection has certain heart protection effects against Endostar combined chemotherapy,and improved the life quality without obvious influence on curative effects.When no cardiac muscle toxic drugs were choosed in Endostar combined chemotherapy with certain indication,and a recommended dose was applied,cardiovascular adverse effects of patients were less serious,and the heart protection effects of Shenqi injection under this situation was not so obvious.
2.Myocardial damage monitoring index should be a routine detection when Endostar is used in combined chemotherapy,and further observation of heat adverse effects should be carried on.
3.Further safety evaluation of usage of Endostar,Endostar combined other myocardia toxic chemotherapy drugs,and Endostar combined anti-epiderm growth factor chemotherapy in a long term should be studied.
引文
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